NM_002944.2:c.6079G>A

ROS1 · NP_002935.2:p.(Glu2027Lys) · NM_002944.2

GRCh37: chr6:117638362 C>T · GRCh38: chr6:117317199 C>T

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Glu2027Lys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002944.2:c.6079G>A (p.Glu2027Lys) is a rare missense variant in the ROS1 gene, absent from all gnomAD population databases (v2.1, v4.1, gnomAD-Canada).

In silico analysis predicts a deleterious effect: REVEL score 0.923 (strongly pathogenic), BayesDel score 0.4228 (moderately pathogenic). SpliceAI predicts no splice impact (max delta 0.15).

This variant has been reported once in COSMIC (COSV107471754) as a somatic alteration and is classified as Uncertain Significance in ClinVar (VariationID 2443073, 1 submitter, no assertion criteria provided).

No variant-specific functional studies, case-control data, segregation data, or de novo observations were identified. OncoKB reports Unknown Oncogenic Effect.

Under generic ACMG/AMP 2015 criteria, this variant meets PM2 (supporting: absent from population databases) and PP3 (supporting: in silico prediction of deleterious effect). All other assessed criteria are not met or not applicable.

With two supporting-level pathogenic criteria (PM2_supporting + PP3_supporting) and no benign criteria met, the evidence is insufficient to classify this variant as likely pathogenic. The variant remains a Variant of Uncertain Significance per ACMG/AMP 2015 classification rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_002944.2:c.6079G>A is a missense substitution (p.Glu2027Lys). PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant does not fall into any PVS1 bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	No pathogenic or likely pathogenic variant with the same amino acid change (p.Glu2027Lys) has been established in ClinVar or the literature. No comparator exists to apply PS1.	clinvar
PS2	Not met	No de novo observation has been reported for NM_002944.2:c.6079G>A. No parental testing data are available.
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. No publications with functional data for p.Glu2027Lys were found.	oncokb
PS4	Not met	No case-control studies demonstrating enrichment of NM_002944.2:c.6079G>A in affected individuals versus controls are available. The variant is absent from gnomAD, precluding statistical comparison.
PS5	N/A	PS5 is used for autosomal recessive or X-linked disorders where a pathogenic variant is found in trans. Insufficient data to apply; ROS1-associated phenotypes are not established as recessive.
PM1	Not met	Position 2027 does not lie within a statistically significant mutational hotspot in ROS1. Cancer Hotspots analysis returned no significant enrichment at this residue.
PM2	Met	NM_002944.2:c.6079G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant not observed in large population cohorts. Under generic ACMG/AMP rules, absence from population databases supports PM2 at supporting level.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic or likely pathogenic missense variant at the same amino acid residue (Glu2027) with a different amino acid change was identified in ClinVar. PM5 candidate harvesting returned zero same-residue comparators.	pm5_candidates clinvar
PM6	Not met	No de novo observation has been reported for NM_002944.2:c.6079G>A. PM6 requires a confirmed de novo event, which is not available.
PP1	Not met	No co-segregation data are available for NM_002944.2:c.6079G>A. No family studies reporting segregation of this variant with disease have been identified.
PP2	Not met	Missense constraint data for ROS1 are not available (HCI prior lookup returned 'gene_not_supported'). Without evidence that ROS1 has a low rate of benign missense variation, PP2 cannot be applied.
PP3	Met	REVEL predicts a damaging score of 0.923 for NM_002944.2:c.6079G>A (p.Glu2027Lys), well above the 0.75 threshold for pathogenic prediction. BayesDel score of 0.4228 provides moderate additional support. SpliceAI predicts no splice impact (max delta 0.15). The preponderance of in silico evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available for this adjudication. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease. Without clinical context, this criterion cannot be assessed.
PP5	N/A	PP5 is used for autosomal recessive disorders when a pathogenic variant is found in trans. ROS1 is not established as a recessive disease gene.
BA1	Not met	NM_002944.2:c.6079G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires allele frequency >1%, which is not met.	gnomad_v2 gnomad_v4
BS1	Not met	NM_002944.2:c.6079G>A is absent from gnomAD. BS1 requires allele frequency >0.3%, which is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on observation of NM_002944.2:c.6079G>A in healthy adult individuals. The variant is absent from gnomAD, precluding assessment of its presence in presumed healthy controls.
BS3	Not met	No functional studies demonstrating a neutral or benign effect of p.Glu2027Lys have been identified. OncoKB reports Unknown Oncogenic Effect with no benign functional evidence.	oncokb
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease. BS4 requires evidence that the variant does not segregate with the phenotype.
BP1	Not met	Although ROS1 loss of function is supported as a disease mechanism per the PVS1 gene context literature review, the evidence does not establish that only truncating variants cause disease. Published germline studies of ROS1 report both missense and splice site variants in affected individuals (PMID:32906649). BP1 requires that primarily truncating variants are known to cause disease, which is not clearly established for ROS1.
BP2	Not met	No evidence that NM_002944.2:c.6079G>A has been observed in trans with a known pathogenic variant in ROS1. BP2 is typically applied in recessive disorders, which are not established for ROS1.
BP4	Not met	REVEL predicts a damaging score of 0.923, strongly inconsistent with a benign in silico profile. While SpliceAI shows no splice impact (max delta 0.15), the REVEL score alone precludes application of BP4, which requires multiple lines of computational evidence suggesting no impact. The overall in silico profile supports a deleterious effect rather than a benign one.	revel bayesdel spliceai
BP5	Not met	No alternate molecular cause for the observed phenotype has been identified in a case carrying NM_002944.2:c.6079G>A. No case-level data with an alternate molecular diagnosis are available.
BP6	Not met	ClinVar reports NM_002944.2:c.6079G>A as Uncertain Significance by a single submitter (Salgia Laboratory, City of Hope) with no assertion criteria provided. BP6 requires a reputable source to classify the variant as benign, which is not met.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_002944.2:c.6079G>A is a missense variant (p.Glu2027Lys), not synonymous.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions. This is a substitution variant.
PM3	N/A	PM3 applies to autosomal recessive disorders with a pathogenic variant in trans. No established recessive disease association for ROS1.
PM4	N/A	PM4 applies to non-repeat in-frame indels or stop-loss variants. This is a substitution variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.